Efficacy of immune checkpoint inhibitors in microsatellite unstable/mismatch repair-deficient advanced pancreatic adenocarcinoma: An AGEO European Cohort.
Authors: Lorenzo Pilla, Lina Sayah, Kathrin Heinrich, Volker Kunzmann, Alice Boileve, Geert A. Cirkel, Sara Lonardi, Benoist Chibaudel, Anthony Turpin, Tamar Beller, Vincent Hautefeuille, Caterina Vivaldi, Thibault Mazard, Lucile Bauguion, Monica Niger, Gerald W. Prager, Clélia Coutzac, Benedikt Westphalen, Edouard Auclin, Julien Taieb
Journal: Journal of Clinical Oncology (2023)

4148 Background: Immune checkpoint inhibitors (ICI) have been approved for the use in solid tumors with MSI/dMMR. Nevertheless, the outcome of patients (pts) with MSI/dMMR pancreatic ductal adenocarcinoma (PDAC) seems poorer when compared to other malignancies. This multi-institutional analysis aimed to assess the efficacy and tolerability of ICIs in a large real-world cohort of pts with MSI/dMMR PDAC. Methods: Retrospective data were collected for pts with MSI/dMMR PDAC treated with ICIs from February 2016 to May 2022 in 16 different centers across Europe and Israel. Progression-free survival (PFS) and overall survival (OS) were calculated from the start of treatment, and objective response (OR) and disease control rate (DCR) were measured according to RECIST V1.1. Results: We identified 31 pts with metastatic MSI/dMMR PDAC. The mean age was 62.1 years (range: 37-82), 45.1% were female and ECOG PS status was predominantly 0 or 1 (83.9%). At the time of ICI treatment 1 pt had locally advanced and 30 had metastatic disease. MSH2/MSH6 deficiency (def) was found in 9 cases, MLH1/PMS2 def in 7, MSH 6 def in 4, MSH 2 def in 3, PMS2 def in 3 and MLH1/MSH6/PMS2 def and, a CpG highland methylator phenotype in 1 pt. MMR status was not available in 4 pts. Germline mutation testing was performed in 20/31 pts (64.5%) and Lynch syndrome was diagnosed in 8 pts (45%). Nineteen pts received pembrolizumab, 8 received nivolumab, 1 received lodapolimab and 3 received ipilimumab/nivolumab (ipi/nivo). The mean number of prior lines of chemotherapy was 1.5 (range 0-4). Among the 31 pts in this analysis, 15 (48,4%) had an OR (3: complete response and 12 partial response) and 6 (19,3%) had stable disease, resulting in a DCR of 67.7%. Ten pts had disease progression (PD) (32.3%). Median PFS was 26.7 months and median OS was not reached with median follow-up (FU) of 18 months. Median duration of response was not reached (95%CI:24.1-NR). Analysis of all responders, with a follow up of 12 months or more (n:14), showed that 100% of them maintained their response. In addition 71% of the pts of this cohort are still alive with a median time of follow up since the diagnosis of metastatic disease of 39.9 months. After ICIs discontinuation, 6 pts received chemotherapy. One pt who had PD after 15 months of pembrolizumab switched to ipi/nivo and achieved a CR. Immunotherapy was generally well tolerated; No Grade 3-5 adverse events (AEs) were reported and no therapy discontinuation due an adverse event was observed. Conclusions: This retrospective analysis suggests that ICIs are effective and well tolerated in pts with MSI/dMMR advanced PDAC. Hence, our work supports the use of PD-1 inhibition in this group of pts with high unmet medical need.